1. Field of the Invention
The present application relates to a hepatic targeted drug delivery system, a process for preparing the same and a method for treating liver cancer.
2. Description of the Related Art
Primary liver cancer is one of the most leading causes of death in China, which is only exceeded by gastric cancer and accounts for 45% of the total death caused by liver cancer all around the world. In addition, the five-year survival rate is merely 5%.
At present, treatment for liver cancer mainly depends on organ transplantation, radiotherapy, chemotherapy and the like. However, liver transplantation is limited by the shortage of donors and the potential immunologic rejection, while the radiotherapy always causes directly damage to bile duct. Therefore, the chemotherapy has become the mainstream for liver cancer treatment. However, the conventional chemotherapy is ineffective, mostly due to the disadvantages of short half-life time in blood stream, high overall clearance rate and poor selectivity for the desired site. In addition, liver has the ability to resist drugs. Low dosage of drugs is ineffective for liver cancer treatment while high dosage may cause toxicity for other organs. Therefore, the development of controlled release and hepatic targeted drug delivery system is primarily important.
Recently, hepatic targeted drug delivery system has attracted much attention because it provides a high degree of selectivity to liver, enhances the uptake ability of drug-loaded nanoparticles into target sites, reduces drug doses and significantly decreases drug toxicity.
However, the development of hepatic targeted drug delivery system is a bit slow. Some researchers have attempted to increase the tissue specificity of drug carriers by coupling with targeting agents, such as monoclonal antibodies. However, antibodies are costly and difficult to be obtained. In addition, as most of them come from mice, the bio-security becomes the major concerns.
In recent years, the receptor-mediated hepatic targeted drug delivery system has attracted more attention because it is a promising way to transfer drug to the desired sites. Once a ligand is bound to a receptor, a ligand-receptor complex is rapidly internalized and the receptor recycles back to the surface (Ciechanover, A., Schwartz, A L. Lodish, H. F. Sorting and recycling of cell surface receptors and endocytosed ligands: the asialoglycoprotein and transferrin receptors. J. Cell. Biochem., 1983, 23(1-4), 107-130). Asialoglycoprotein receptor (ASGPR) is known as to be present on hepatocytes and several human hepatoma cell lines which shows a strongly affinity with galactose residues. Extensive studies have focused on the ASGPR-mediated hepatic targeted drug delivery system. For example, Hsing-Wen Sung, et al. in U.S. Pat. No. 7,348,030 B 1 discloses nanoparticles for targeting hepatoma cells. In particular, nanoparticles comprised by poly(γ-glutamic acid)-block-polylactide and conjugated with galactosamine are disclosed. The in vitro experimental results show that these nanoparticles have high affinity to hepatoma cells. However, it has been reported that there are inhibitors in serum of a subject in pathologic status, which lead to low recognition of ASGPR for galactose residues (Stockert R. J., Morell A. G. Hepatic binding protein: the galactose-specific receptor of mammalian hepatocytes, Hepatology, 1983, 3: 750-757). Therefore, the development of a new hepatic targeted ligand instead of the conventional one is very necessary.
Liquorice mainly distributes in the west of China and has been widely used in the prescription of traditional Chinese medicine. Glycyrrhizin and glycyrrhetinic acid can be isolated from its root easily. In 1991, Negishi confirmed that the rat liver cell membrane contains a large number of binding sites for glycyrrhetinic acid and a small number of binding sites for glycyrrhizin (Negishi M., Irie A., Nagata N., et al. Specific binding of glycyrrhetinic acid to the rat liver membrane, Biochim. Biophys. Acta., 1991, 1066: 77-82). Since then, studies on the hepatic targeted drug delivery system mediated by glycyrrhizin and glycyrrhetinic acid has drawn the focus of most researchers. Subsequently, some Chinese and foreign researchers reported that when liposome or serum albumin was modified with glycyrrhizin/glycyrrhetinic acid, it exhibits a considerably high affinity to liver than that of the unmodified ones (Sayoko Osaka, Hideki Tsuji, Hiroshi Kiwada. Uptake of liposomes surface-modified with glycyrrhizin by primary cultures rat hepatocytes, Biol. Pham. Bull., 1994, 17: 940-943; Sheng-jun Mao, Shi-xiang Hou, Ru He, et al. Uptake of albumin nanoparticle surface modified with glycyrrhizin by primary cultured rat hepatocytes. World J. Gastroentenol., 2005, 11: 3075-3079). However, liposome is limited as a drug delivery carrier due to several factors such as the rapid uptake by the reticuloendothelial system (RES), quick clearance from blood stream and the leakage of their loading content before reaching the targeting sites. Therefore, some new drug carriers should be taken into consideration.
During the last decade, biomedical polymers, especially the biodegradable and biocompatible polymers develop rapidly, promoting the development of drug controlled release field. Moreover, with the cross-integration of materials science, biomedicine and molecular biology, the developing process has also been accelerated. Polymeric nanoparticles can protect drugs from being uptaken by the RES, thereby enhancing drug stability, increasing the efficacy and prolonging the circulation time in blood, and the loaded drug can be targeted to the desired sites with a sustained release profile. Currently, much attention has been paid to the nanoparticles made from natural polysaccharide such as chitosan or its derivatives and sodium alginate. Moreover, synthetic poly(amino acid)-ester and polyester are also gained considerable attention.
The hepatic targeted drug delivery system mediated by glycyrrhizin or glycyrrhetinic acid (components of traditional Chinese drug) is seldom reported in the world except in China. For example, Yingli ZHENG, et al. in Chinese patent application No. 200410052767.5 discloses glycyrrhizin-modified chitosan nanoparticles and process for preparing the same. Yiming LIU, et al. in Chinese patent application No. 200710062813.3 discloses a process for preparing glycyrrhetate-modified chitosan/carboxyl-chitosan complex nanoparticles.
Up to now, the glycyrrhetinic acid-mediated hepatic targeted drug delivery system has solely been reported by Zhi YUAN, et al. in Chinese patent application No. 200510015172.7.